The ATP7B-classical form with hypoceruloplasminemia has primary hepatopathy and late extra-hepatic complications, while the severe hepatic form is free from ATP7B mutation and hypoceruloplasminemia, and silently progresses to liver failure.
Wilson's disease is an autosomal recessive disorder characterized by liver disease and/or neurologic deficits due to copper accumulation and is caused by pathogenic mutations in the ATP7B gene.
Four rodent models with ATP7B gene defects have been described - the Long-Evans Cinnamon (LEC) rat, inbred mouse models (toxic milk (tx), the Jackson Laboratory toxic milk (tx-j)), and the genetically engineered ATP7B<sup>-/-</sup> (knockout) mouse - all of which develop liver disease to different extents.
Decreased biliary copper excretion and reduced incorporation of copper into apoceruloplasmin caused by defunctionalization of ATP7B protein lead to accumulation of copper in many tissues and organs, including liver, brain, and cornea, finally resulting in liver disease and extrapyramidal symptoms.
In this cell-free system, copper induced thiol modifications of three abundant mitochondrial membrane proteins, and this correlated with reversible intramitochondrial membrane crosslinking, which was also observed in liver mitochondria from Atp7b–/– rats.